Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV) types 6 and 11, is characterized by repeated growth of pre-malignant tumors, with significant morbidity and mortality. Standard treatment is surgical removal but patients can require >100 surgical procedures to maintain their airway, at a cost of >$100 million U.S. dollars yearly. The major question driving our studies is: what prevents RRP patients from mounting an effective immune response to HPV? These HPVs induce extremely high levels of the pro-inflammatory cytokine IL-36? in papilloma tissues, which paradoxically fails to trigger an effective activating innate response and the subsequent immune clearance of these lesions. We are currently conducting a phase IIB clinical trial of celecoxib in RRP, and this proposed study will permit us to address this mechanism in vivo. Our long-term goal is to use our knowledge of the immune response in RRP to develop better therapies for this disease. These studies may also provide critical insight into why some patients with high risk HPV infections of the oropharynx fail to clear the infection and ultimately develop cancer. Specific Aims: Three aims will test the hypothesis that RRP patients have a defect in IL-36? mediated activation of the innate immune response caused, at least in part, by expression of PGE2 in the airway are: 1A) Determine the effect of IL-36? on the expression and release of cytokines/chemokines by laryngeal keratinocytes from RRP patients, and the effects of elevated COX-2/PGE2 on this modulation; 1B) Determine the effect of both IL-36? and exogenous PGE2 on maturation and the expression of pro/anti-inflammatory cytokine/chemokines by Langerhans cells; 2): Determine the signal transduction pathways that mediate expression and release of IL-36? in laryngeal keratinocytes and Langerhans cells, and the impact of concurrent PGE2 signaling on those pathways; and 3). Determine if patterns of altered pro/anti-inflammatory cytokine/chemokine expression in Aim I parallel those in serum and laryngeal tissue from RRP patients enrolled in an ongoing, phase IIB clinical trial of celecoxib therapy. Innovation: We will test for the first time, the novel concept that a host-specific, constitutive, and elevated expression of PGE2 suppresses the local HPV-induced inflammatory response and contributes to a bias in innate immune signaling in RRP patients. We have the unique opportunity through our clinical trial of celecoxib to compare our in vitro studies with in vivo responses. These studies should identify novel targets that could change the existing surgical approach to treat RRP patients to medical immune-based therapies that would be less costly, reduce morbidity, have the potential to cure this disease, and also provide critical and much needed insight into why some patients with high risk HPV infection develop cancer of the oropharynx.